Abstract
A limitation in the application of pluripotent stem cell-derived cardiomyocytes (PSC-CMs) is the failure of these cells to achieve full functional maturity. The mechanisms by which directed differentiation differs from endogenous development, leading to consequent PSC-CM maturation arrest, remain unclear. Here, we generate a single-cell RNA sequencing (scRNA-seq) reference of mouse in vivo CM maturation with extensive sampling of previously difficult-to-isolate perinatal time periods. We subsequently generate isogenic embryonic stem cells to create an in vitro scRNA-seq reference of PSC-CM-directed differentiation. Through trajectory reconstruction, we identify an endogenous perinatal maturation program that is poorly recapitulated in vitro. By comparison with published human datasets, we identify a network of nine transcription factors (TFs) whose targets are consistently dysregulated in PSC-CMs across species. Notably, these TFs are only partially activated in common ex vivo approaches to engineer PSC-CM maturation. Our study can be leveraged toward improving the clinical viability of PSC-CMs.
Original language | English (US) |
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Article number | 112330 |
Journal | Cell Reports |
Volume | 42 |
Issue number | 4 |
DOIs | |
State | Published - Apr 25 2023 |
Keywords
- CP: Stem cell research
- cardiomyocyte
- maturation
- single-cell RNA sequencing
- stem cells
- tissue engineering
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology